Prospective Randomized Phase II Parallel Study of Vinorelbine Maintenance Therapy versus Best Supportive Care in Advanced Non-Small Cell Lung Cancer.

Background
Maintenance strategy has been used to improve survival in non-small cell lung cancer (NSCLC). We investigated whether switch maintenance therapy with vinorelbine improved progression free survival (PFS) after first-line chemotherapy with gemcitabine plus carboplatin.


Materials and Methods
In this single blind, parallel, phase 2, randomized trial, patients with NSCLC pathology, age >18 years, Eastern Cooperative Oncology Group (ECOG) performance status (PS) score of 0-2, and advanced stage (IIIB and IV) were treated with up to 6 cycles of gemcitabine 1250 mg/m2 (day 1 and 8) plus carboplatin AUC 5 (day 1) every 3 weeks. Patients who did not show progression after first-line chemotherapy were randomly assigned to receive switch maintenance with vinorelbine (25 mg/m2, day 1, 15) or the best supportive care until disease progression.


Results
A total of 100 patients were registered, of whom 34 had a non-progressive response to first-line chemotherapy and randomly received maintenance vinorelbine (n=19) or best supportive care (n=15). The hazard ratio of PFS in the vinorelbine group relative to the best supportive care group was 1.097 (95% confidence interval = 0.479-2.510; P-value =0.827). There was no significant difference between the overall survival for the two groups (P=0.068).


Conclusion
Switch maintenance strategies are beneficial, but defining the right candidates for treatment is a problem. Moreover, the trial designs do not always reflect the real-world considerations. Switch maintenance therapy with vinorelbine, though had tolerable toxicity, did not improve PFS in patients with NSCLC. Therefore, other agents should be considered in this setting.


INTRODUCTION
Since 1987, lung cancer has been the leading cause of cancer-related deaths in women and men worldwide. (1) In Iran (situated in southwest Asia / Middle East), lung cancer ranks 2 nd in men and 3 rd in women as the cause of cancer-related death (2). Nearly, 85% of newly diagnosed lung cancers have a non-small cell lung cancer (NSCLC) pathology (3,4), and are locally advanced (inoperable stage IIIB) or metastatic (stage IV) at the time of diagnosis (5).
Systemic standard platinum-based chemotherapy as firstline treatment is recommended for patients with advanced stage disease (6). With combination platinum-based chemotherapy regimens, the median of overall survival (OS) and median progression free survival (PFS) are [8][9][10][11] and 4 months, respectively (7). Recently, maintenance strategies, which are defined as opportunities for extending the duration of first-line treatment (continuing one or all the drugs previously administered as first-line) or switching to a different and non-cross-resistant agent, are introduced immediately after completion of first-line treatment. They have received great attention, especially in patients who benefit from the initial treatment, in order to prolong the duration of disease control (8,9).
Administration of a single agent as maintenance therapy following 4-6 cycles of combination chemotherapy has been studied in some randomized clinical trials.
In contrast, a meta-analysis of randomized trials demonstrated significantly increased PFS but not OS by using the maintenance strategy (15). Navelbine (vinorelbine, NVB) is the first semi synthetic 5'-nor-vincaalkaloid that is manufactured from alkaloids extracted from the rosy periwinkle, Catharanthus roseus (16). It has been shown to have a good level of activity in different solid tumors (17). Vinorelbine Tartrate alone and in combination with other cytotoxic or targeted agents are approved by the Food and Drug Administration (FDA) for the treatment of NSCLC (18,19). It has also been used as second-line chemotherapy in progressive disease (20).
We designed this study to examine whether vinorelbine switch maintenance therapy would improve PFS in patients with advanced stage NSCLC whose disease had not progressed after the initial treatment with gemcitabine plus carboplatin.  (21). Other eligibility criteria included at least one unidimensionally measurable or assessable disease, adequate bone marrow reserve, serum creatinine less than or equal to 1.5 mg/dL or a calculated creatinine clearance greater than or equal to 60 mL/min, bilirubin level less than or equal to 2.0 mg/dL, (1,000-1,500/dL) and/or had a platelet count of 75,000-100,000/dL. If the neutrophil or platelet count was less than 1,000/dL and 75,000/dL, respectively chemotherapy was postponed. Notably, in this real world study, the dosage of the cytotoxic agent was adjusted by the clinicians based on the patient's age, frailty, or other adverse events during the course of treatment. However, any patient who developed a severe reaction was taken off the protocol.

MATERIALS AND METHODS
Toxicity assessment was based on the "Common Terminology Criteria for Adverse Events" (CTCAE) version 3.0 (24). Criteria for withdrawal from the study included unacceptable toxicity as determined by the treating physician in consultation with the study coordinator, a delay in treatment greater than 2 weeks, requirement for palliative radiotherapy, or patient refusal.

Statistical analysis :
The primary end point of this phase 2 study was PFS.
The secondary objectives were OS and adverse events.
All confidence intervals (CIs) for parameters to be estimated were constructed with a significance level of alpha = 0.05 (a 95% confidence level). Patients were assigned to the vinorelbine (n=19) or best supportive care (n=15) group, after being centrally randomized to a 1:1 ratio during the 3rd week after the first-line chemotherapy using the Stata 9.0 (StataCorp, College Station, TX, USA) statistical software.
For testing the differences in the categorical variables between the two groups, the chi-square test or Fisher's exact test was used. The difference in the quantitative variables of the two groups was compared using the Student's t-test or non-parametric Mann-Whitney test. We tested the hypothesis that an 18 months survival rate could be expected in 10 % of the best supportive care group and 20% of the maintenance group, using a sample size that was determined using a significance level of 5% for alpha.
Kaplan Meier's survival curves were obtained, and the logrank test was used to assess the significance of differences in PFS and OS between the two study groups. PFS was calculated from the date of registration in maintenance phase to the date of progression or death. OS was calculated from the date of registration in maintenance phase to the date of death. A COX-PH regression model was used to estimate the hazard ratios and their 95% CIs (confidence intervals). 34 patients were finally randomized after assuming an accrual period of 3 years; a potential follow-up for 2 years for the last patients and a type I error rate of 0/5. The study was stopped on March 20, 2013. All analysis was performed using SPSS version 21.

Patient characteristics and Initial treatment:
A total of 100 patients were enrolled in this study ( Figure 1). The mean age of the patients was 59.73 years.  Six deaths (6%) occurred after the first-line treatment that was unrelated to the induction chemotherapy (five were due to severe physical state alteration and one was an unknown cause).

Maintenance treatment delivery
The number of vinorelbine cycles administered was as follows: one to three in 10 patients, four to eight in 7 patients and nine in 2 patients. The mean duration of vinorelbine chemotherapy was 10 weeks, and the median of total delivered dose was 240 mg (range 100-1090 mg).

Toxicity
The grade 3 toxicities that occurred in at least 33

Response in maintenance group
Of  Post-maintenance or best supportive care therapies used are listed in Table 3. Three patients in the best supportive care group and two patients in the vinorelbine group were not assessable due to discontinuation of Vinorelbine therapy.

DISCUSSION
This study was conducted to determine the benefits of therefore, best chance of cure or disease relapse prevention would be to use all effective chemotherapy drugs (28).
In the SATURN study (29), a significant increase in OS was observed only in patients who showed SD response after first-line chemotherapy. In our study too, PFS was longer in patients who had SD response to first-line chemotherapy and received switch maintenance chemotherapy with vinorelbine than in patients who had SD response and were in the other group, but the difference was not significant. The findings of the SATURN study suggest that SD might actually be progressive SD and early maintenance therapy actually is a part of early second line chemotherapy.
Westeel et al. (10) showed no PFS benefit of vinorelbine maintenance therapy in NSCLC after platinum-based initial chemotherapy, which is partially similar to our findings. However, in our study anemia was higher but incidences of grade 3, 4 leukopenia, thrombocytopenia, sepsis, pulmonary toxicity, and neuropathy were less.